5-cyano-2-aminopyrimidine derivatives

Abstract

Pyrimidines of formula (1) are describedwhereinAr is an optionally substituted aromatic or heteroaromatic group;R1 is a hydrogen atom or a straight or branched chain alkyl group;R2 is a -X1-R3 group where X1 is a direct bond or a linker atom or group, andR3 is an optionally substituted aliphatic, cycloaliphatic, heteroaliphatic, heterocycloaliphatic, aromatic or heteroaromatic group;and the salts, solvates, hydrates and N-oxides thereof.The compounds are selective KDR Kinase and/or FGFr Kinase inhibitors and are of use in the prophylaxis and treatment of disease states assoicated with angiogenesis.

What is claimed is:  
     
       1. A compound of formula (1):                    
       wherein 
       Ar is an optionally substituted aromatic or heteroaromatic group;  
       R 1  is a hydrogen atom or a straight or branched chain alkyl group;  
       R 2  is a group —X 1 —R 3  in which X 1  is a direct bond, and R 3  is an optionally substituted aliphatic optionally interrupted by one or two heteroatoms or heteroatom-containing groups, cycloalkyl, heterocyclyl, aromatic or heteroaromatic group;  
       and the salts, solvates, hydrates and N-oxides thereof.  
     
     
       2. A compound according to  claim 1  in which R 3  is an optionally substituted aromatic or heteroaromatic group, said heteroaromatic group containing one or two ring oxygen, sulphur and/or nitrogen atoms. 
     
     
       3. A compound according to  claim 2  wherein R 3  is a phenyl, thienyl, thiazolyl, indolyl or pyridyl group optionally substituted by one, two or three —R 4b  or —Alk(R 4b ) m  substituents in which R 4b  is a halogen atom, or an amino (—NH 2 ), substituted amino, nitro, cyano, hydroxyl (—OH), substituted hydroxyl, formyl, carboxyl (—CO 2 H), CO 2 Alk 1  (wherein Alk 1  is a straight or branched, optionally substituted C 1-8 alkyl group, a C 6-12 arylC 1-8 alkyl group, a C 6-12 aryl group, a C 6-12 aryloxyC 1-8 alkyl group, an optionally substituted C 1-8 alkanoyloxyC 1-8 alkyl group, or a C 6-12 aroyloxyC 1-8 alkyl group), thiol (—SH), substituted thiol, —COR 5  (where R 5  is a —Alk(R 4 ) m , aryl, optionally substituted monocyclic or bicyclic C 6-12  aromatic group, or an optionally substituted C 1-9  heteroaromatic group), —CSR 5 , —SO 3 H, —SO 2 R 5 , —SO 2 NH 2 , —SO 2 NHR 5 , —SO 2 N(R 5 ) 2 , —CONH 2 , —CSNH 2 , —CONHR 5 , —CSNHR 5 , —CON(R 5 ) 2 , —CSN(R 5 ) 2 , —NHSO 2 H, —NHSO 2 R 5 , —N(SO 2 R 5 ) 2 , —NHSO 2 NH 2 , —NHSO 2 NHR 5 , NHSO 2 N (R 5 ) 2 ,—NHCOR 5 , —NHCONH 2 , —NHCONHR 5 , —NHCON (R 5 ) 2 , —NHCSR 5 , —NHC(O)OR 5 , or optionally substituted cycloalkyl, heterocyclyl, aryl, monocyclic or bicyclic C 6-12  aromatic group, or C 1-9  heteroaromatic group; Alk is a straight or branched C 1-6  alkylene, C 2-6 , alkenylene or C 2-6 , alkynylene chain, optionally interrupted by one, two or three —O— or —S— atoms or groups selected from —S(O)—, —S(O) 2 — or —N(R 6 )— (where R 6  is a hydrogen atom or a straight or branched chain C 1-6  alkyl group); and m is zero or an integer 1, 2 or 3. 
     
     
       4. A compound which is: 
       5-Cyano-4-phenyl-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;  
       5-Cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]-4-(4-methoxcarbonylphenyl)pyrimidine-2-amine;  
       5-Cyano-4-(4-hydroxymethylphenyl)-N-(3,4,5-trimethoxy-phenyl)pyrimidine-2-amine;  
       5-Cyano-4[(4-N,N-diethylaminomethyl)phenyl]-N-(3,4,5-trimethoxyphenyl)pyrimidine-2-amine;  
       5-Cyano-4-[2-(3(R)-dimethylaminopyrrolidin-1-yl)pyridin-5-yl]-N-(indazol-5-yl)pydmidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(indazol-5-yl)-pyrimidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3,4,5-trimethoxy-phenyl)pyrimidine-2-amine;  
       5-Cyano-N-[4-(2-N,N-diethylaminoethylaminocarboxy)phenyl]-4-phenylpyrimidine-2-amine;  
       5-Cyano-4-phenyl-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}-pyrimidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-4(1,2,3-triazol-1-yl)-phenyl]pyrimidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-ethylimidazol-1-yl)ethyl]phenyl}pyrimidine-2-amine;  
       N-[3-(5-Cyano-4-thiophen-2-ylpyrimidin-2-ylamino)phenyl]-4-(4-methylpiperazin-1-ylmethyl)benzamide;  
       4-[3-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-(2-methyl-imidazol-1-yl)ethyl]phenyl}pyrimidine-2-amino;  
       5-Cyano-4-[4-(imiadzol-1-yl)methyl]phenyl-N-(3,4,5-trimethoxy-phenyl)-pyrimidine-2-amino;  
       and the salts, solvates, hydrates and N-oxides thereof. 
     
     
       5. A compound which is: 
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4(1,2,4-triazol-1-yl)phenyl]pyrimidine-2-amine;  
       5-Cyano-N-[4-(1,2,4-triazol-1-yl)phenyl]-4-[4-(1-dimethylamino-1-methylethyl)phenyl]pyrimidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-{4-[2-piperidin-1-ylethyl]phenyl}pyrimidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-imidazol-1-ylethyl)phenyl]pyrimidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[4-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-[3-(2-morpholinoethyl)phenyl]pyrimidine-2-amine;  
       5-Cyano-4-[4-(1-methyl-1-pyrrolidin-1-ylethyl)phenyl]-N-(4-fluorophenyl)pyrimidine-2-amine;  
       5-Cyano-4-{2-([2-(diethylamino)ethyl]amino)pyridin-5-yl}-N-(4-fluorophenyl)pyrimidine-2-amine;  
       4-[4-(1-Amino-1-methylethyl)phenyl]-5-cyano-N-(3-fluorophenyl)pyrimidine-2-amine;  
       and the salts, solvates, hydrates and N-oxides thereof.